Hydroxyacetic ester derivatives, preparation method and use as synthesis intermediates

ABSTRACT

Methyl (R)-2-(R 1 OSO 2 )-2-(2-chlorophenyl)acetates useful as intermediates in the preparation of methyl (S)-2(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]-5-pyridyl)acetate.

This application is a 371 of PCT/FR98/02082, filed Sep. 29, 1998, now WO99/18110.

The present invention concerns, in a general fashion, new derivatives ofhydroxyacetic esters, and their use as synthesis intermediates.

More specially, the object of the invention is the sulfonyloxyaceticesters with the general formula:

in which R₁ represents a benzyl group, a C₁-C₄ alkyl, which may besubstituted by one or several halogen atoms, such as chlorine orbromine, or a phenyl group, which may be substituted by one or severalhalogen atoms or by one or several linear or branched C₁-C₄ alkyl groupsor by a nitro group.

In particular, the invention concerns formula-I compounds in which R₁represents a methyl, ethyl, propyl, trifluoromethyl, benzyl, phenyl,chlorophenyl, tolyl, trimethylphenyl, triisopropylphenyl, dichlorophenylin particular 2,5-dichlorophenyl or nitrophenyl, in particularp-nitrophenyl, group.

Formula-I compounds have demonstrated themselves to be particularlyuseful as intermediates, notably for the synthesis of methyl(S)-2(2-chlorophenyl)-2(4,5,6,7-tetrahydrothieno[3,2-c]-5-pyridyl)acetateor clopidrogel.

This enantiomer, which has the following structural formula:

is known for its therapeutic value, notably for its inhibition ofplatelet aggregation and antithrombotic properties.

In patent EP 0465358, a process is described for the preparation of the(R) and (S) enantiomers of2-(halogenophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]-5-pyridyl)acetateof a C₁-C₄ alkyl, using 2-arylacetic esters with a labile group in the 2position.

According to this process:

a) racemic a C₁-C₄ alkyl 2-(halogenophenyl)-2-halogeno or a C₁-C₄alkylsulfonyloxy, or C₆-C₁₀ alkyl arylsulfonyloxy)acetate is coupledwith 4,5,6,7-tetrahydrothieno[3,2-c]pyridine in the form of a base orsalt to obtain a racemic compound.

b) the racemate thus formed is resolved by recrystallising opticallyactive acid salts to obtain the desired (R) or (S) enantiomers.

However, the only example given of this process started from racemicmethyl 2(2-chlorophenyl)-2-chloroacetate for the final preparation ofclopidogrel and no precise indication or example was given to illustratethe preparation of a C₁-C₄ alkyl 2-(halophenyl)-2-(bromo oralkylsulfonyloxy or arylsulfonyloxy)-acetate.

According to this example, clopidogrel is obtained by carrying out thefollowing 5 steps, starting from a 2-hydroxyacetic ester:

a) and b) reaction of racemic 2(2-chlorophenyl)-2-hydroxyacetic acidwith phosphorus pentachloride and esterification with methanol to formracemic methyl 2-(2-chlorophenyl)-2-chloroacetate with a 45% yield,

c) coupling of the methyl 2-(2-chlorophenyl)-2-chloroacetate formed inthis way, with 4,5,6,7-tetrahydrothieno[3,2-c]pyridine in the presenceof potassium carbonate, which yields racemic methyl2-(4,5,6,7-tetrahydrothieno[3,2-c]-5-pyridyl)-2(2-chlorophenyl)-acetate,with a mean yield of 80%,

d) resolution of the racemate obtained by salification withcamphosulphonic acid (yield: 88% in terms of the salt desired)

e) regeneration of clopidogrel in basic form by treating thecamphosulphonic salt in question with sodium bicarbonate

Using this process, clopidogrel is obtained with a chemical yield of upto 30% from 2(2-chlorophenyl)-2-hydroxyacetic acid.

During the preliminary trials carried out in the context of the presentinvention, an attempt was made to prepare clopidogrel or its (R)enantiomer by means of an analogous reaction to that described in thepatent already referred to, but starting from the (R) or (S) enantiomerof methyl 2(2-chlorophenyl)-2-chloroacetate.

However, all the tests performed in methanol, acetonitrile or ethylacetate as solvent at a temperature between room temperature and 65° C.,with 1 or 2 equivalents of 4,5,6,7-tetrahydrothieno[3,2-c]pyridineeither in the form of the base or in the form of the hydrochloride, withor without sodium bicarbonate, led to the production of 72 to 88% ofracemic methyl2(2-chlorophenyl)-2(4,5,6,7-tetrahydrothieno[3,2-c]-5-pyridyl)acetate.

Other tests carried out with heating to 80° C. and using methyl(S)-2(2-chlorophenyl)-2-chloroacetate and4,5,6,7-tetrahydrothieno[3,2-c]pyridine in the presence of sodiumcarbonate and in a solvent mixture of methylisobutyl ketone/wateryielded methyl(R)-2(4,5,6,7-tetrahydrothieno[3,2-c]-5-pyridyl)-2(chlorophenyl)acetatewith an entantiomeric excess of only 20%.

Consequently, the development of a process for the preparation ofclopidogrel from 4,5,6,7-tetrahydrothieno[3,2-c]pyridine using astereoselective method, which involves as few steps as possible andproviding an appreciable yield of the desired compound remains ofincontestable importance.

It has been discovered rather surprisingly, according to the invention,that clopidogrel can be obtained in just 3 steps from(R)-2(2-chlorophenyl)-2-hydroxyacetic acid with a global yield of theorder of 80% by replacing themethyl-(R)-2(2-chlorophenyl)-2-halogenoacetate, bymethyl-(R)-2(2-chlorophenyl)-acetate, which has a sulfonyloxy group inthe 2 position, i.e. a compound with the above formula I.

This process is all the more surprising because:

A) the 2-methanesulfonyloxy groups and 2-toluenesulfonyloxy groups ofcarboxyl esters are known to undergo racemisation when they are involvedin a nucleophilic substitution by an amine function (Angew. Chem. Int.Ed. Eng. 22 (1983), no. 1 pp 65-66).

These claims have been confirmed in Tetrahedron, Vol. 47, no. 7, pp1109-1135 (1991), where it is reported that the 2-methanesulfonyloxy and2-p-toluenesulfonyloxy esters of carboxylic acids are inappropriatesubstrates for a stereoselective nucleophilic substitution reaction inthe 2 position.

Similar observations have been published in Leibigs. Ann. Chem. 1986, p.314-433, where yields of <30% are reported as being obtained during thesubstitution of methyl-2-p-toluenesulfonyloxy- ormethyl-2-methanesulfonyloxy-propionate with benzylamine.

B) The (R) and (S) enantiomers of 2-sulphonyloxyacetic esters, whichinclude an additional 2-phenyl group, are known to produce compoundswith considerably reduced stereoselectivity after nucleophilicsubstitution in the 2-position.

For example, Tetrahedron, Vol. 44, no. 17, pp 5583-5595 (1988) reportsthe substitution of derivatives of (S) or (R)methyl-2-triflyloxy-2-X-acetate by O-benzylhydroxylamine indichloromethane as a solvent and at a temperature between 0° C. and roomtemperature in order to form the (R) and (S) acetic esters of2-O-benzylhydroxylamino-2-X respectively. As is known, the triflyl groupdesignates the trifluoromethylsulfonyl radical.

This reaction is found to be highly selective in the case of esters inwhich X represents an alkyl group, which may be substituted, such asmethyl or benzyl (enantiomeric excess, ee≧95%), but has much lowerselectivity when X represents the phenyl group since the enantiomericexcess of the corresponding (R)-2-O-benzylhydroxylamino-2-phenyl esteris no more than 50%. Very similar results have been reported after otherexperiments carried out using 2-sulphonyloxy derivatives of2-phenylacetic esters.

Thus:

a) Tetrahedron Letters, Vol. 31, no. 21, pp 2953-2956 (1990) describesthe substitution reaction of the methyl (S)-2-triflyloxy-2-X-acetateesters with t-butyloxycarbonylhydrazine or BOC-hydrazine, indichloromethane and at 0° C., to form (R)-2-BOC-hydrazinyl-2-X-aceticesters.

The selectivity of this reaction has also been shown to be veryconsiderable when X represents an alkyl group, which may be substituted,such as methyl, isobutyl or benzyl (ee>95%), but in contrast, verylimited when X represents phenyl (ee: 28%).

b) Tetrahedron, Vol. 48, no. 15, pp 3007-3020 (1992) reports thesubstitution of methyl (S)-2-nosyloxy-2-X-acetate derivatives with anazido group, the reaction taking place in dichloromethane and at roomtemperature, in order to form (R)-2-azido-2-X acetic esters.

Once more, the substitution of the 2-sulfonyloxy group, in this case thenosyloxy group, takes place in a highly selective manner when Xrepresents an alkyl group, which may be substituted, such as methyl,isopropyl, sec-butyl or benzyl (ee>92%), but disappointing when Xrepresents the phenyl group (ee: 35%).

These latter findings actually led the authors of the publication inquestion to conclude that “the phenyl group is well known for reducingstereoselectivity when the esters of 2-nosyloxy and 2-triflyloxy estersare substituted by different classes of nucleophilic agents”. As isknown, the nosyl group designates the p-nitrophenylsulfonyl radical.

The sulfonyloxy derivatives of formula-I acetic esters that have shownthemselves to be particularly interesting synthesis intermediates,notably for the preparation of clopidogrel are:

methyl (R)-2-benzenesulfonyloxy-2(2-chlorophenyl)acetate

methyl (R)-2(2-chlorophenyl)-2(p-toluenesulfonyloxy)acetate

methyl (R)-2(2-chlorophenyl)-2-methanesulfonyloxy acetate

methyl (R)-2(4-chlorobenzenesulfonyloxyl)-2-(2-chlorophenyl)acetate

methyl (R)-2(2-chlorophenyl)-2(2,4,6-trimethylbenzenesulfonyloxy)acetate

methyl(R)-2(2-chlorophenyl)-2(2,4,6-triisopropylbenzenesulfonyloxy)acetate

methyl (R)-2(2-chlorophenyl)-2(4-nitrobenzenesulfonyloxy)acetate

methyl (R)-2(2-chlorophenyl)-2(2,5-dichlorobenzenesulfonyloxy)acetate

In particular, the following are preferred

methyl (R)-2-benzenesulfonyloxy-2(2-chlorophenyl)acetate

methyl (R)-2(2-chlorophenyl)-2(2,4,6-trimethylbenzenesulfonyloxy)acetate

methyl(R)-2(2-chlorophenyl)-2(2,4,6-triisopropylbenzenesulfonyloxy)acetate

methyl (R)-2(2-chlorophenyl)-2(4-nitrobenzenesulfonyloxy)acetate

methyl (R)-2(4-chlorobenzenesulfonyloxyl)-2(2-chlorophenyl)acetate

methyl (R)-2(2-chlorophenyl)-2(2,5-dichlorobenzenesulfonyloxy)acetate.

The sulphonyloxy derivatives of the invention can be obtained byreacting the (R)-2(2-chlorophenyl)-2-hydroxy acetic ester with theformula:

with a sulphonyl anhydride or halogenide, with the general formula

R₁—SO₂—R₂  III

in which R₂ represents an OSO₂—R₁ group or, preferably, a halogen atomsuch as chlorine or bromine, and R₁ has the same significance as before,in the presence of a lithium salt and an aromatic amine which acts bothas a catalyst and acid acceptor such as pyridine or4-dimethylaminopyridine, which yields the desired compound.

The reaction in question is generally carried out in an aprotic solvent,such as a C₁-C₄aliphatic hydrocarbide, preferably halogenated, forinstance dichloromethane, dichloroethane, chloroform, carbontetrachloride or tetrachloroethane, and at a temperature between 0° C.and room temperature.

In addition, the aromatic amine, preferably C₆-C₁₀, is used instoichiometric quantity or preferably a slight excess which can reach1.2 molar equivalent in terms of the formula-III compound.

The coupling reaction of the formula-II and formula-III compounds inwhich R₂ represents a halogen atom, can give rise to a side reactionwhich results in the formation of a halogenated derivative i.e. a methyl2(2-chlorophenyl)-2-halogenoacetate derivative.

However, it was fortuitously noticed that the presence of a lithium saltin the reaction mixture makes it possible to reduce this side reactionconsiderably and consequently to obtain high proportions of theformula-I compound.

By way of example, the reaction between methyl(R)-2(2-chlorophenyl)-2-hydroxyacetate with p-nitrobenzenesulfonylchloride or p-toluenesulfonyl chloride in dichloromethane at 20° C. andin the presence of pyridine and lithium perchlorate, produces a yield of92% of methyl (R)-2(2-chlorophenyl)-2(p-nitrobenzenesulfonyloxy)acetateand a yield of 85% of methyl(R)(2-chlorophenyl)-2(p-toluenesulfonyloxy)acetate respectively after 5hours, whereas the same reaction, conducted in the absence of lithiumperchlorate produces yields of only 28% and 30% of the end productrespectively.

This lithium salt, which can be for example, lithium perchlorate(LiClO₄) or lithium tetrafluoroborate (LiBF₄), is used in astoechiometric quantity. However, it is preferable to take a slightexcess of this lithium salt, that is up to 1.2 molar equivalent in termsof the formula-III compound.

As for the formula-II ester, it can be obtained using a non-racematingreaction by esterifying (R)-2(2-chlorophenyl)-2-hydroxyacetic acid or(R)-2-chloro-mandelic acid, which is a commercial product, with methanoland in the presence of a strong acid, such as sulfuric acid.

According to a variant of the above process, formula-I sulphonyloxyderivatives can also be prepared by reacting the formula-II ester with aformula-III halogenide in the presence of 4-dimethylaminopyridine ascatalyst and another acid acceptor, such as an aliphatic amine, forexample triethylamine to produce the desired compound.

The reaction is generally conducted at a temperature of −10° C. to +10°C., preferably at 0° C., and in an aprotic solvent, such as one of thosealready mentioned, notably dichloromethane.

The processes described above make it possible to obtain formula-Isulfonyloxy derivatives with particularly good yields, usually of theorder of 90 to 98% and with quite remarkable enantiomeric excesses of>99%.

As previously indicated, the sulfonyloxy derivatives of the inventioncan be used notably for the preparation of clopidogrel.

In consequence, another object of the invention concerns the preparationof clopidogrel by a process in which4,5,6,7-tetrahydrothieno[3,2-c]pyridine in the form of a base or saltwith a formula-I sulphonyloxy derivative in the presence of a basicagent used alone or in aqueous solution, which yields the desiredcompound.

The reaction medium used is usually a polar solvent, such as a C₂-C₅aliphatic ester, for example ethyl or isopropyl acetate, a C₁-C₄aliphatic alcohol, N,N-dimethylformamide, a C₄-C₆ cyclic ester or aC₂-C₆ aliphatic ester such as tetrahydrofuran or isopropyl ether, aC₂-C₈ aliphatic ketone, for example methylisobutylketone or, preferably,a non-polar solvent, such as a C₁-C₄ halogenated aliphatic hydrocarbon,for example dichloromethane, dichloroethane, chloroform, carbontetrachloride or tetrachloroethane or a C₆-C₁₀ aromatic hydrocarbon, forexample benzene, toluene or a xylene so that a two-phase system isformed if water is present in the reaction medium. In this latter case,if necessary, a phase-transfer catalyst can be used, such as aquaternary ammonium, a phosphonium salt or a crown ether.

Similarly, the basic agent can be a carbonate of an alkali metal, suchas sodium or potassium carbonate, or a bicarbonate of an alkali metal,for instance sodium or potassium bicarbonate, and the reaction can beconducted at a temperature ranging from ambient temperature to thereflux temperature of the medium used.

As for the 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, a known compound, itis used in a stoechiometric quantity but usually and preferably in anexcess which can be as much as 2.5 molar equivalents in terms of theformula-I sulfonyloxy derivative.

By conducting this latter reaction in toluene, methylisobutylketone orisopropyl acetate at a temperature of 80° C. over about 4 hours, it ispossible to obtain clopidogrel with a chemical yield in excess of 95%and with an enantiomeric excess of between 80 and 88%.

Using dichloromethane as the solvent and at a temperature of 40° C.:

a) the percentage converted into clopidogrel can reach 94 to 95% in 5hours with an enantiomeric excess of 96%.

b) starting from methyl(R)-2(4-chlorobenzenesulfonyloxy)-2(2-chlorophenyl)acetate, theconversion into clopidogrel reaches 100% after 10 hours and theenantiomeric excess is 96%.

c) starting from methyl(R)-2(2-chlorophenyl)-2(4-nitrobenzenesulfonyloxy)acetate, theconversion into clopidogrel reaches 100% after 30 minutes and theenantiomeric excess is >98%.

Using an alternative pathway, clopidogrel can also be prepared fromsulphonyloxy derivatives of the invention and 2(thien-2-yl)ethylamine.

Consequently, the invention also applies to the preparation ofclopidogrel according to a process in which:

a) 2(thien-2-yl)ethylamine in the form of the base or salt is reactedwith a formula-I sulphonyloxy derivative in the presence in a basicagent used alone or in aqueous solution, to form methyl(+)-(S)-α(2(thien-2-yl)ethylamino)-α-(2-chlorophenyl)acetate, which hasthe formula:

b) the thienylethylamine derivative thus formed is reacted with anformylation agent and cyclised in the presence of an acid, which yieldsthe desired compound.

The formylation agent used in the above process can be:

either formic aldehyde or any compound generally known to release it ina reactive form, such as for example its hydrate or its polymerisationderivatives. These formylation agents can be considered to be preferredin the context of the invention.

or compounds with the general formula:

R₃—CH₂—R₄  V

in which R₃ represents a halogen atom, a C₁-C₄ alkyloxy group, a C₁-C₄alkylthio group or an amino group and R₄ represents a C₁-C₄ alkoxygroup, a C₁-C₄ alkylthio group, a C₂-C₅ alkoxycarbonyl orphenoxycarbonyl group

or heterocyclic compounds with the general formula:

in which Z represents O, NH, or S, such as s-trioxane.

The step involving the use of 2(thien-2-yl)ethylamine, a known compound,can be conducted under the same operating conditions as those describedpreviously for the use of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine

The formylation and cyclization step can give rise to intermediatecompounds, such as a hydroxymethyleneamine or a heterocycle of thetrimethylenetriamine type, as reported in patent EP 0 466 569.

Consequently, the reactions with the formylation and cyclization agentcan be carried out successively, possibly by isolating the intermediatecompounds in question, or conversely, they can take placesimultaneously.

When the reactions occur successively, the step involving theformylation agent can be carried out optionally in the presence of anether, a hydrocarbon solvent, such as benzene, toluene, xylene orpetroleum ether or of a halogenated solvent, such as methylene chlorideor dichloroethane.

The cyclisation is then carried out in a polar solvent, such as water,an alcohol, dimethylformamide or in a mixture of these solvents.

As the formylation agent, formic aldehyde is generally preferred andthis can be added to the reaction medium in the form of an aqueoussolution.

The acid can be an organic or inorganic acid, in general a strong acid,such as sulphuric acid, or a hydracid, such as hydrochloric acid, or asulphonic acid, such as methanesulphonic acid.

When the reactions are carried out simultaneously, the reaction mediumconsists of a polar solvent, such as water or an alcohol, and the acid,which can be inorganic or organic, is added to the medium, preferably instiochiometric quantity in terms of the formula-IV compound employed. Inthis case, this acid is a strong acid which can be simply added to themedium in the form of its salt with the formula-IV compound. An acidicsolvent such as formic acid or acetic acid can also be used, the formercombined with paraformaldehyde being particularly preferred.

Clopidogrel is obtained according to the invention, that is by using thevarious methods described above, can then be purified if necessary, by aconventional method using a recrystallisation process or bychromatographic procedures.

The following non-exhaustive examples illustrate the invention.

PREPARATION Methyl (R)-2-hydroxy-2(2-chlorophenyl)acetate

A 1000-ml reactor fitted with a double jacket and a valve in the bottom,a mechanical stirrer, a thermometer and a condenser is loaded with 120 g(0.643 mole) of (R)-2-hydroxy-2(2-chlorophenyl)acetic acid, 480 ml ofmethanol and 4.8 g of 95% sulfuric acid. The solution obtained is thenheated under reflux for 2 hours and the excess methanol is theneliminated under reduced pressure. The oily residue is then taken up in650 ml of dichloromethane and 240 g of an aqueous solution of 10%potassium carbonate.

After decanting, the chlorinated phase is washed with 200 ml of waterand then concentrated under reduced pressure.

In this manner, 124.4 g of methyl (R)-2-hydroxy-2(2-chlorophenyl)acetateis obtained in the form of a colourless oil.

Yield: 94%

Optical purity by liquid chromatography of the chiral phase: >99%.

NMR (CDCl₃): 7.4-7.2 ppm (multiplet 4 aromatic protons) 5.57 ppm(singlet, 1 CH proton) 3.76 ppm (singlet, 3 OCH₃ protons) 3.59 ppm (widesinglet, 1 OH proton)

EXAMPLES 1 TO 7 Methyl (R)-2-benzenesulfonyloxy-2(2-chlorophenyl)acetateExample 1

In a dry, 100-ml tricol round-bottomed flask, fitted with a magneticstirrer, a condenser and a thermometer and operating under an atmosphereof nitrogen, is taken 3.81 g (36 mmoles) of lithium perchlorate, 30mmoles of benzenesulfonyl chloride and 45 ml of dichloroethane.

To the solution obtained, is added 2.9 ml (36 mmoles) of pyridine. Thenon-uniform white reaction medium is then stirred for 15 minutes beforeadding 6.0 g of methyl (R)-2-hydroxy-2(2-chlorophenyl)acetate dissolvedin 15 ml of dichloroethane. The milky reaction mixture obtained isstirred for 5 hours and then poured over a stirred mixture of 120 ml of1N hydrochloric acid and 240 ml of dichloromethane. After decanting, thechlorinated phase is washed with 120 ml of water and then concentratedunder reduced pressure. The sulphonate thus formed takes the form of acolourless, viscous liquid. Purification on a silica column yields ananalytically pure sample. In this manner, methyl(R)-2-benzenesulfonyloxy-2(2-chlorophenyl)acetate is obtained.

Yield: 90%

Optical purity: >99%

[α]₅₈₉ ²⁵: −53° (2%, methanol)

NMR (CDCl₃) 7.88 ppm (doublet of triplets, 2 aromatic protons) 7.63 to7.55 ppm (multiplet, 1 aromatic proton) 7.50 to 7.38 ppm (multiplet, 3aromatic protons) 7.33 to 7.17 ppm (multiplet, 3 aromatic protons) 6.30ppm (singlet, 1 (CH) proton) 3.70 ppm (singlet, 1 (OCH₃) proton).

Following the same process as that described previously, the followingcompounds have been prepared:

(R)-2(2-chlorophenyl)-2(4-p-toluenesulfonyloxy)acetate Example 2

Yield: 85%

Optical purity: >99%

[α]₅₈₉ ²⁵−58.3° (2%, methanol)

NMR (CDCl₃) 7.75 to 7.25 ppm (multiplets, 8 aromatic protons) 5.79 ppm(singlet, 1 (CH—O) proton) 3.67 ppm (singlet, 3 (OCH₃) protons) 2.41 ppm(singlet, 3 (CH₃-phenyl) protons)

Methyl (R)-2(2-chlorophenyl)-2-methanesulfonyloxy acetate Example 3

Yield: 87%

Optical purity: >99%

[α]₅₈₉ ²⁵−75.6° (2%, methanol)

NMR (CDCl₃) 7.49 to 7.28 ppm (multiplets, 4 aromatic protons) 6.40 ppm(singlet, 1 (CH) proton) 3.79 ppm (singlet, 3 (OCH₃) protons) 3.14 ppm(singlet, 3 (SO₂CH₃) protons)

Methyl (R)-2(4-chlorobenzenesulfonyloxy)-2(2-chlorophenyl)acetateExample 4

Yield: 90%

Optical purity: >99%

NMR (CDCl₃) 7.8 and 7.43 ppm (2 doublets, 4 aromatic protons) 7.42 to7.18 ppm (multiplet, 4 aromatic protons) 6.31 ppm (singlet, 1 (CH)proton) 3.73 ppm (singlet, 3 (OCH₃) protons)

Methyl (R)-2(2-chlorophenyl)-2(2,4,6-trimethylbenzenesulfonyloxy)acetateExample 5

Yield: 93%

Optical purity: >99%

NMR (CDCl₃) 7.50 to 7.20 ppm (multiplet, 4 aromatic protons) 6.92 ppm(singlet, 2 aromatic protons) 6.21 ppm (singlet, 1 (CH) proton) 3.69 ppm(singlet, 3 (OCH₃) protons) 2.62 ppm (singlet, 6 (CH₃) protons) 2.30 ppm(singlet, 3 (CH₃) protons)

Methyl(R)-2(2-chlorophenyl)-2(2,4,6-triisopropylbenzenesulfonyloxy)acetateExample 6

Yield: 93%

Optical purity: >99%

NMR (CDCl₃) 7.50 to 7.20 ppm (multiplet, 4 aromatic protons) 7.14 ppm(singlet, 2 aromatic protons) 6.25 ppm (singlet, 1 (CH) proton) 4.09 ppm(septuplet, 2 (2CH-isopropyl) protons) 3.71 ppm (singlet, 3 (OCH₃)protons) 2.85 ppm (septuplet, 1 (CH isopropyl) proton) 1.24 ppm(doublet, 6 (2 CH₃) protons) 1.22 ppm (doublet, 6 (2 CH₃) protons) 1.10ppm (doublet, 6 (2 CH₃) protons)

Methyl (R)-2(2-chlorophenyl)-2(4-nitrobenzenesulfonyloxy)acetate Example7

Yield: 92%

Optical purity: >99%

NMR (CDCl₃) 8.29 and 8.06 ppm (2 doublets, 4 aromatic protons) 7.40 to7.15 ppm (multiplet, 4 aromatic protons) 6.37 ppm (singlet, 1 (CH)proton) 3.74 ppm (singlet, 3 (OCH₃) protons)

Example 8 Methyl (R)-2-benzenesulfonyloxy-2(2-chlorophenyl)acetate

In a dry, tricol round-bottomed flask, fitted with a double-jacket, amagnetic stirrer, a condenser and a thermometer and operating under anatmosphere of nitrogen, is taken 0.72 g (6 mmoles) of4-dimethylaminopyridine, 12.0 g (60 mmoles) of methyl(R)-2-hydroxy-2(2-chlorophenyl)acetate, 6.06 g (60 mmoles) oftriethylamine and then 20 ml of dichloromethane. The colourless solutionobtained is cooled to 0° C. and then, operating at this temperature, 60mmoles of benzenesulfonyl chloride in solution in 30 ml ofdichloromethane is added. The reaction mixture is stirred for 3 hours at0° C. and then tipped onto a stirred mixture consisting of 240 ml of 1Nhydrochloric acid and 240 ml of dichloromethane.

After decanting, the chlorinated phase is washed with 120 ml of waterand then concentrated under reduced pressure.

The sulfonate thus formed takes the form of a colourless viscous liquid.An analytically pure sample is obtained after purifying on a silicacolumn.

In this manner, methyl (R)-2-benzenesulfonyloxy-2(2-chlorophenyl)acetateis obtained:

Yield: 97%

Optical purity: >99%

[α]₅₈₉ ²⁵−53° (2%, methanol)

Following the same process as that described above, the followingcompounds are obtained:

Methyl (R)-2(2-chlorophenyl)-2(4-nitrobenzenesulfonyloxy)acetate Example9

Yield: 88%

Optical purity: >99%

Methyl (R)-2(2-chlorophenyl)-2(2,5-dichlorobenzenesulfonyloxy)acetateExample 10

Yield: 95%

Optical purity: >99%

NMR (CDCl₃) 7.98 ppm (doublet, 1 aromatic proton) 7.15 to 7.50 ppm(multiplets, 6 aromatic protons) 6.38 ppm (singlet, 1 (CH) proton) 3.74ppm (singlet, 3 (OCH₃) protons)

Example 11 Methyl (R)-2-benzenesulfonyloxy-2(2-chlorophenyl)acetate

This compound was obtained using the method described in Example 8, butreplacing the dichloromethane by toluene.

Yield: 95%

Example 12 Methyl (R)-2-benzenesulfonyloxy-2(2-chlorophenyl)acetate

In a dry, tricol round-bottomed flask, fitted as in Example 8 is taken0.72 g (6 mmoles; 0.1 equivalent) of 4-dimethylaminopyridine, 12.0 g (60mmoles; 1 equivalent) of methyl (R)-2-hydroxy-2(2-chlorophenyl)acetateand 7.8 g (78 mmoles; 1.3 equivalent) of triethylamine and 20 ml ofdichloromethane. The colourless solution obtained is cooled to 0° C. andthen, operating at this temperature, 6.06 g (60 mmoles; 1 equivalent) ofbenzenesulfonyl chloride in solution in 30 ml of dichloromethane. Thereaction mixture is stirred for 3 hours at 0° C. and then tipped onto astirred mixture consisting of 240 ml of 1N hydrochloric acid and 240 mlof dichloromethane, while stirring this mixture.

After decanting, the chlorinated phase is washed with dilutehydrochloric acid and then with water, before being concentrated underreduced pressure. An analytically pure sample is obtained afterpurifying on a silica column.

In this manner, methyl (R)-2-benzenesulfonyloxy-2(2-chlorophenyl)acetateis obtained:

Yield: 98%

Optical purity: 100% (S(+) enantiomer not detected).

Example 13 Methyl(S)-2(2-chlorophenyl)-2(4,5,6,7-tetrahydrothieno[3,2-c]-5-pyridyl)acetate

In a dry, 50-ml tricol round-bottomed flask, fitted with a doublejacket, a magnetic stirrer, a condenser and a thermometer, is taken Ymmoles of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine in solution in 7.5 mlof solvent and 2.85 g of a 30% aqueous solution of potassium carbonate.After stirring for 10 minutes, 5 mmoles of the formula-I compound,previously dissolved in 2.5 ml of solvent, is added.

The two-phase medium thus obtained is heated under reflux for the timeindicated and then cooled to 70° C. and decanted.

In this manner, methyl(S)-2(2-chlorophenyl)-2(4,5,6,7-tetrahydrothieno[3,2-c]-5-pyridyl)acetateor clopidogrel is obtained

NMR (CDCl₃) 7.70 ppm (multiplet, 1 aromatic proton of benzene) 7.41 ppm(multiplet, 1 aromatic proton of benzene) 7.33 to 7.22 ppm (multiplet, 2aromatic protons of benzene) 7.06 ppm (doublet, 1 aromatic proton ofthiophene) 6.67 ppm (doublet, 1 aromatic proton of thiophene) 4.93 ppm(singlet, 1 CHCO proton) 3.73 ppm (singlet, 3 OCH₃ protons) 3.76 and3.64 ppm (2 doublets, 2 CH₃ protons) 2.89 ppm (singlet, 4 2CH₂ protons)

Depending on the formula-I compounds used, the concentrations of4,5,6,7-tetrahydrothieno[3,2-c]pyridine used, the yields obtained usingthe above solvents and reaction times are as follows:

Formula-I Clopidogrel compound Y Reaction time Optical purity R1(mmoles) Solvent (h) Yield (%) (%) Phenyl 5 toluene 4.5 85 90 (1.7 g; 1equivalent) Phenyl 6 dichloromethane 5 94.5 96.2 (1.2 equivalent) Phenyl 12.5 dichloromethane 5 98.5 89 (2.5 equivalent) 4-chlorophenyl 6dichloromethane 10 about 100 96 4-nitrophenyl 6 dichloromethane 0.5about 100 >98

Example 14 Methyl(S)-2(2-chlorophenyl)-2(4,5,6,7-tetrahydrothieno[3,2-c]-5-pyridyl)acetate

In a 50-ml tricol round-bottomed flask, fitted with a double-jacket, amagnetic stirrer, a condenser and a thermometer is taken 1.2 mmoles of4,5,6,7-tetrahydrothieno[3,2-c]pyridine in solution in 7.5 ml ofdichloromethane and 2.85 g of a 30% aqueous solution of potassiumcarbonate. After stirring for 10 minutes, 5 mmoles of methyl(R)-2(2-chlorophenyl)-2(2,5-dichlorobenzenesulfonyloxy)acetate,previously dissolved in 2.5 ml of solvent is added.

The two-phase medium thus obtained is heated under reflux for 3.5 hours,cooled to 70° C. and then decanted.

In this manner, methyl(S)-2(2-chlorophenyl)-2(4,5,6,7-tetrahydrothieno[3,2-c]-5-pyridyl)acetateis obtained.

Yield: 89%

Optical purity: 96%

Example 15 Methyl(S)-2(2-chlorophenyl)-2(4,5,6,7-tetrahydrothieno[3,2-c]-5-pyridyl)hemisulphateor clopidogrel hemisulphate

a) Methyl (+)-(S)-α-(2-thien-2-yl)ethylamino)-α-(2-chlorophenyl)acetate

In a 250-ml reactor, fitted with a double jacket, a motor-drivenstirrer, a condenser and a thermometer is taken 7.62 g of2(thien-2-yl)ethylamine (0.06 mole; 1.2 molar equivalent in terms of thesulphonyloxy derivative) in solution in 67.5 ml of dichloromethane andan aqueous solution of 7.0 g of potassium bicarbonate (0.07 mole; 1.4equivalent in terms of the sulfonyloxy derivative) in 30 ml of water.After stirring for 5 minutes, 0.05 mole (1 equivalent) of the formula-Icompound is added, dissolved in 40 ml dichloromethane.

The two-phase medium thus obtained is heated under reflux for the timeindicated, cooled and then decanted and the (+) methyl(S)-α(2-thien-2-yl)ethylamino-α(2-chlorophenyl)acetate (formula IV) iscollected.

Depending on the formula-I compounds used and with the above reactiontimes, the following yields are obtained:

Formula-I compound Formula IV-compound R1 Reaction time (h) Yield (%)Optical purity (%) methyl 29 65 76 phenyl 22 71 92 4-chlorophenyl 11 9492 4-nitrophenyl 2 99 95 2,5-dichlorophenyl 6 98 97

b) Clopidogrel Hemisulphate

While stirring, 20.5 g of (+) methyl(S)-α(2-thien-2-yl)ethylamino-α(2-chlorophenyl)acetate in solution in200 ml of methylene chloride is added over 25 minutes to 40 ml of 30%(w/w) of an aqueous solution of formic aldehyde.

After stirring for 3 hours, the organic phase is decanted, washed withwater, dried and the solvent evaporated. The residue is dissolved in 50ml of methylene chloride and the solution, at a temperature of 60° C.,is added to 100 ml of anhydrous N,N-dimethylformamide containing 6Nhydrochloric acid. After one hour and a half, the solvents areeliminated by distilling under reduced pressure and the residue isdissolved in 200 ml of methylene chloride and 100 ml water.

Sodium bicarbonate is added to release the base from its hydrochloride,the organic phase decanted, dried and concentrated under reducedpressure, which yields clopidogrel in the form of the free base.

The hemisulphate of this basic compound is then formed in 150 ml ofacetone by reacting with 4.9 g of concentrated sulphuric acid (96%).

In this manner, 17 g of clopidogrel hemisulphate is obtained.

[α]_(D) ²⁰=53° (C=1, methanol).

What is claimed is:
 1. A process for preparing a compound of the formula

having an optical purity equal to or greater than 80% which comprisesreacting 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, in the formn of thebase or a salt with a compound of the formula:

in the presence of a basic agent used alone or in an aqueous solution,wherein R₁ is benzyl, C₁-C₄ alkyl, which may be substituted by one orseveral halogen atoms, or R₁ is a phenyl group, which may be substitutedby one or several halogen atoms or by one or several linear or branchedC₁-C₄ alkyl groups or by a nitro group.
 2. A process according to claim1 wherein the basic agent is a carbonate or a bicarbonate of an alkalimetal.
 3. A process according to claim 1 wherein the reaction occurs ina polar or non-polar solvent.
 4. A process according to claim 3 whereinthe reaction takes place at a temperature ranging from room temperatureto the reflux temperature of the reaction medium.
 5. A process accordingto claim 3 wherein the solvent is a C₂-C₅ aliphatic ester, a C₁-C₄aliphatic alcohol, N,N-dimethylformamide, a C₄-C₆ cyclic ester or aC₂-C₆ aliphatic ester, a C₂-C₈ aliphatic ketone, a C₁-C₄ halogenatedaliphatic hydrocarbon, or a C₆-C₁₀ aromatic hydrocarbon.
 6. A processaccording to claim 1 wherein R₁ is selected from the group consisting ofphenyl, 4-chlorophenyl, 4-nitrophenyl and 3,5-dichlorophenyl.
 7. Aprocess according to claim 6 wherein the basic agent is an aqueoussolution of potassium carbonate.
 8. A process according to claim 7wherein the reaction is carried out in a solvent selected from tolueneand dichloromethane under reflux.